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Pharmacokinetic Guided Dose Escalation and Dose Confirmation With Oral Decitabine and Oral Cytidine Deaminase Inhibitor (CDAi) in Patients With Myelodysplastic Syndromes (MDS)

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ClinicalTrials.gov Identifier: NCT02103478
Recruitment Status : Completed
First Posted : April 4, 2014
Results First Posted : October 19, 2020
Last Update Posted : October 19, 2020
Sponsor:
Information provided by (Responsible Party):
Astex Pharmaceuticals, Inc.

Tracking Information
First Submitted Date  ICMJE March 20, 2014
First Posted Date  ICMJE April 4, 2014
Results First Submitted Date  ICMJE August 4, 2020
Results First Posted Date  ICMJE October 19, 2020
Last Update Posted Date October 19, 2020
Actual Study Start Date  ICMJE October 28, 2014
Actual Primary Completion Date June 5, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 11, 2020)
  • Mean Decitabine Area Under the Concentration Versus Time Curve (AUC0-t) on Day 5 by Cohort in Phase 1 [ Time Frame: Day 5 ]
    Mean AUC0-t of oral decitabine given with cedazuridine (E7727) following IV decitabine 20 mg/m^2 infusion on Day 5. AUCs were calculated by the linear up/log down method using the measured concentration-time values above the BQL (below the limit of quantification).
  • Mean Decitabine Area Under the Plasma Concentration Versus Time Curve Ratio (5-day AUC0-t) in Phase 2 [ Time Frame: Pre-dose to Day 5 ]
    Decitabine 5-day AUC ratio following IV decitabine 20 mg/m^2 infusion versus concomitant oral administration of decitabine + cedazuridine (E7727) or ASTX727 in the dose combination and fixed-dose combination stages, respectively. AUC0-t (the area under the concentration-time curve from time zero to the time of the last (tlast) quantifiable concentration (Ct)) by dose/cohort and course/days was used for estimating decitabine cumulative 5-day AUC0-t exposures.
  • Number of Participants With Dose-limiting Toxicity in Phase 1 [ Time Frame: Up to Day 28 in Course 1 (28 days per course) ]
    Number of participants with protocol-specified dose-limiting toxicities (DLTs) in the dose escalation stage. DLTs were defined using the Common Terminology Criteria for Adverse Events Version 4.0 (CTCAEv4.0), specifically ≥ Grade 3 non-hematologic toxicity (except Grade 3 nausea, vomiting, or diarrhea that is controllable by anti-emetics or optimal therapy or related to underlying disease or disease progression), specific Grade 3 laboratory tests, related prolonged Grade 4 thrombocytopenia or neutropenia that was not present prior to dosing, does not resolve within 14 days, and is not related to underlying disease, or any toxicity related to study treatment that results in treatment delays of >4 weeks after Day 28.
  • Mean Maximum %LINE Demethylation in Phase 2 [ Time Frame: Pre-dose to Day 28 in Course 2 (28 days per Course) ]
    Mean maximum % long interspread nuclear element-1 (LINE-1) demethylation after oral decitabine + cedazuridine (E7727) or ASTX727 (Course 1 or Course 2 - Treatment) compared with IV decitabine 20 mg/m^2 (Course 1 or Course 2 - IV Decitabine) in the dose confirmation and fixed-dose combination stages, respectively. Least squares mean of maximum %LINE-1 methylation change from baseline.
  • Number of Participants With Overall Response in Phase 2 [ Time Frame: Up to approximately 29 months (data for Phase 2 participants as of 05 June 2018 data cut-off) ]
    The evaluation of response was based on International Working Group (IWG) 2006 MDS Response Criteria, with overall response calculated as number of participants with complete response+partial response+marrow complete response+hematological improvement (CR+PR+mCR+HI).
Original Primary Outcome Measures  ICMJE
 (submitted: April 1, 2014)
  • Dose Escalation Hematology testing [ Time Frame: Hematology daily during the first week and then weekly for an average of courses (approximately 6 months) ]
    Complete blood count with differential
  • Dose Escalation; Number of subjects with adverse events and the type of adverse events [ Time Frame: At each visit (daily in week 1 of course 1) then weekly through course 6 (an average of 6 months) ]
    Type of adverse event includes severity and causality
  • Dose Escalation; Number of subjects with changes to physical examinations [ Time Frame: Assessed at the end of course 1 in dose escalation to determine the next cohort/stage of the study then as needed in the study through course 6 (an average of 6 months) ]
    Symptom directed physical examinations will be performed at each visit
  • Dose Confirmation Clinical Laboratory testing [ Time Frame: Hematology daily during the first week and then weekly through course 6; serum chemistry weekly through course 6 (an average of 6 months) ]
    Complete blood count and differential, serum chemistry
  • Dose Confirmation; Number of subjects with adverse events and the type of adverse events [ Time Frame: At each visit (daily in week 1 of course 1 and weekly through course 2 then each course then weekly through course 6) (an average of 6 months) ]
    Type of adverse event includes severity and causality
  • Dose Confirmation; Number of subjects with changes to physical examinations [ Time Frame: Change from baseline to course 6 or last visit if prior to course 6 (an average of 6 months) ]
    Symptom directed physical examinations will be performed at each visit
  • Dose Escalation Serum Chemistry testing [ Time Frame: Weekly through course 6 (an average of 6 months) ]
    Serum Chemistry, electrolytes, liver enzymes, BUN, creatinine
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 11, 2020)
  • Area Under the Concentration Versus Time Curve of Cedazuridine (E7727) and Cedazuridine-epimer [ Time Frame: At specified timepoints from 0 to 24 hours post-dose ]
    AUC is a measure of the plasma concentration of the drug over time (AUC0-8). PK parameters are reported for the dose escalation stage by cohort in Phase 1 and dose confirmation and fixed-dose combination stages in Phase 2.
  • Maximum Observed Plasma Concentration (Cmax) of Cedazuridine (E7727) and Cedazuridine-epimer [ Time Frame: At specific timepoints from 0 to 24 hours post-dose ]
    Cmax is the maximum observed plasma concentration. PK parameters are reported for the dose escalation stage by cohort in Phase 1 and dose confirmation and fixed-dose combination stages in Phase 2.
  • Time to Maximum Observed Plasma Concentration (Tmax) of Cedazuridine (E7727) and Cedazuridine-epimer [ Time Frame: At specific timepoints from 0 to 24 hours post-dose ]
    Tmax is the time to maximum observed plasma concentration. PK parameters are reported for the dose escalation stage by cohort in Phase 1 and the dose confirmation and fixed-dose combination stages in Phase 2.
  • Maximum Observed Plasma Concentration (Cmax) of Decitabine [ Time Frame: At specific timepoints from 0 to 24 hours post-dose ]
    Cmax is the maximum observed plasma concentration. PK parameters for plasma decitabine are reported for the dose escalation stage by cohort in Phase 1 and dose confirmation and fixed-dose combination stages in Phase 2.
  • Time to Maximum Observed Plasma Concentration (Tmax) of Decitabine in Phase 2 [ Time Frame: At specific timepoints from 0 to 24 hours post-dose ]
    Tmax is the time to reach maximum plasma concentration for decitabine. PK parameters for plasma decitabine are reported for the dose confirmation and fixed-dose combination stages.
  • Duration of Complete Response in Phase 1 [ Time Frame: Up to 32 Months ]
    Duration of response (in number of days) was calculated from the first time the response was observed to time of relapse or last time point in the study.
  • Duration of Complete Response in Phase 2 - Kaplan-Meier Estimate [ Time Frame: Up to approximately 29 months (data for Phase 2 participants as of 05 June 2018 data cut-off) ]
    Duration of response (in number of days) was calculated from the first time the response was observed to time of relapse or last time point in the study. Kaplan-Meier estimate for complete response is shown.
  • Mean Maximum %LINE Demethylation in Phase 1 [ Time Frame: Pre-dose to Day 28 in Course 2 (28 days per Course) ]
    Mean maximum % long interspread nuclear element-1 (LINE-1) demethylation decrease from baseline after oral decitabine + cedazuridine (E7727) or ASTX727 compared with IV decitabine 20 mg/m^2 in the dose escalation stage.
  • Number of Participants With Overall Response in Phase 1 [ Time Frame: Up to 32 months ]
    The evaluation of response was based on International Working Group 2006 MDS Response Criteria, with overall response calculated as number of participants with complete response+partial response+marrow complete response+hematological improvement (CR+PR+mCR+HI).
  • Number of Participants With Adverse Events [ Time Frame: Up to 32 months ]
    Number of participants with any treatment-emergent adverse event (AE) and any AE graded ≥3 using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
  • Number of Participants With Hematological Improvement [ Time Frame: Up to 32 months ]
    Hematological improvement was calculated as defined by the IWG 2006 MDS Response Criteria.
  • Number of Participants With Transfusion Independence [ Time Frame: Up to 32 months ]
    Transfusion independence was calculated based on the number of transfusion-dependent participants at baseline who had no red blood cell or platelet transfusions for 56 consecutive days or more after treatment.
  • Number of Participants to Reach Acute Myeloid Leukemia (AML) or Death [ Time Frame: Up to 32 months ]
    Number of participants to reach the event (AML or death), where time to reach AML was calculated as the number of days from the day the participant received the first dose of IV decitabine, oral decitabine + E7727, or the FDC tablet to the date of death or the date of MDS progression to AML as defined by ≥20% blasts in bone marrow or peripheral blood using the World Health Organization classification. Time to AML or death was censored on the last date of contact if a participant was lost to follow up prior to reaching a time-to-event endpoint.
  • Number of Participants With Overall Survival [ Time Frame: Up to 32 months ]
    Overall survival was defined as the number of days from the day the participant received the first dose of IV decitabine, oral decitabine + E7727, or the FDC tablet to the date of death, regardless of cause.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 1, 2014)
  • Dose Escalation and Dose Confirmation-Randomization; AUC, Cmax, Cmin [ Time Frame: Courses 1 and 2 (approximately 2 months) ]
    Serial blood samples will be obtained and analyzed for pharmacokinetic (PK) parameters ( AUC, Cmax, Cmin) during dose escalation and dose confirmation-randomization.
  • Response to treatment [ Time Frame: Prior to every odd course (1, 3, 7) until course 7 (an average of 4 times over 6 months) ]
    Treatment response will be assessed through analysis of peripheral blood and bone marrow aspirations/biopsies prior to the start of course 3, 5 and 7.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Pharmacokinetic Guided Dose Escalation and Dose Confirmation With Oral Decitabine and Oral Cytidine Deaminase Inhibitor (CDAi) in Patients With Myelodysplastic Syndromes (MDS)
Official Title  ICMJE A Phase1-2 Pharmacokinetic Guided Dose-Escalation and Dose-Confirmation Study of ASTX727, a Combination of the Oral Cytidine Deaminase Inhibitor (CDAi) E7727 With Oral Decitabine in Subjects With Myelodysplastic Syndromes (MDS)
Brief Summary This first-in-human, 3-stage, open-label study evaluated the safety and pharmacokinetics of ASTX727, as well as determined the dose for later stages.
Detailed Description The trial was designed to define daily doses of the individual components (cedazuridine [E7727] or decitabine) so that decitabine exposure after oral administration would be comparable to exposure after IV decitabine at the approved daily dose of 20 mg/m^2. The main objective of Phases 1 and 2 was to establish and confirm the doses of the 2 components to be used in the final fixed-dose combination (FDC) product (ASTX727) using mainly pharmacokinetics and pharmacodynamics as endpoints.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Myelodysplastic Syndrome
  • MDS
Intervention  ICMJE
  • Drug: ASTX727 Dose Escalation
    Oral investigational product and approved IV decitabine
    Other Names:
    • cedazuridine (E7727)
    • oral decitabine
    • IV decitabine
  • Drug: ASTX727 Dose Confirmation
    Randomization cross over design for courses 1 and 2
    Other Names:
    • ASTX727 oral (combination of oral E7727 and oral decitabine)
    • IV decitabine
  • Drug: ASTX727 Fixed-Dose Combination
    Fixed-dose investigational product
    Other Name: ASTX727 oral (combination of oral E7727 and oral decitabine)
Study Arms  ICMJE
  • Experimental: Phase 1 Dose Escalation
    Starting cohort was administered 40 mg oral cedazuridine and 20 mg oral decitabine. Participants were enrolled into successive cohorts in which either the cedazuridine or decitabine oral dose was varied in Course 1 Day 2 through Course 1 Day 5 for comparison with a single dose of IV decitabine at 20 mg/m^2 administered on Day 1 by continuous IV infusion over 1 hour (28 days per course).
    Intervention: Drug: ASTX727 Dose Escalation
  • Experimental: Phase 2 Dose Confirmation
    Participants were randomized in a 1:1 ratio to receive either oral cedazuridine (E7727) (100 mg) + decitabine (35 mg) capsules Dailyx5 in Course 1 followed by IV decitabine (20 mg/m^2) Dailyx5 in Course 2 (28 days per course) or the converse. In Courses ≥ 3, participants received cedazuridine and decitabine capsules Dailyx5 in 28-day courses until disease progression, unacceptable toxicity, withdrawal of consent or withdrawal from the study.
    Intervention: Drug: ASTX727 Dose Confirmation
  • Experimental: Phase 2 Fixed-Dose Combination
    Participants were randomized in a 1:1 ratio to receive either the fixed-dose combination (FDC) tablet (100 mg cedazuridine (E7727)/35 mg decitabine) Dailyx5 in Course 1 followed by IV decitabine (20 mg/m^2) Dailyx5 in Course 2 (28 days per course) or the converse. In Courses ≥ 3, all participants received the FDC tablet Dailyx5 in 28-day courses until disease progression, unacceptable toxicity, withdrawal of consent or withdrawal from the study.
    Intervention: Drug: ASTX727 Fixed-Dose Combination
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: October 11, 2020)
130
Original Estimated Enrollment  ICMJE
 (submitted: April 1, 2014)
150
Actual Study Completion Date  ICMJE December 4, 2019
Actual Primary Completion Date June 5, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • International Prognostic Scoring System (IPSS) low, intermediate -1, intermediate-2, or high risk MDS (including chronic myelomonocytic leukemia; CMML) in Dose Escalation and Dose Confirmation-Randomization; only intermediate-2, or high risk MDS in Dose Confirmation-Open Label
  • Eastern Cooperative Oncology Group (ECOG) 0 to 2
  • No major surgery within 2 weeks of starting study treatment
  • No cytotoxic chemotherapy within 2 weeks of starting study treatment
  • Able to swallow pills

Exclusion Criteria:

  • Previous treatment with 2 or more courses of decitabine (all stages) or azacitidine (Dose Confirmation stage only)
  • Treatment with investigational therapy within 2 weeks of study treatment
  • Uncontrolled medical disease(s) or active, uncontrolled infection
  • Diagnosed with acute myeloid leukemia (AML)
  • Active uncontrolled gastric or duodenal ulcer
  • Known history of HIV or hepatitis C or B
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02103478
Other Study ID Numbers  ICMJE ASTX727-01
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Astex Pharmaceuticals, Inc.
Study Sponsor  ICMJE Astex Pharmaceuticals, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Mohammad Azab, MD Astex Pharmaceuticals, Inc.
Study Chair: James Lowder, MD Astex Pharmaceuticals, Inc.
PRS Account Astex Pharmaceuticals, Inc.
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP